Anti-tapeworm infection composition

ABSTRACT

An orally ingestible anti-tapeworm infection composition for mammals which comprises a therapeutically effective non-toxic amount of a compound selected from the class consisting of a base of Formula (I) wherein R is alkyl having from three to eight carbon atoms, R&#39;&#39; is alkyl having from one to 11 carbon atoms, wherein both the Rs attached to the nitrogen atom are the same, and in which the sum of the carbons in Rs and R&#39;&#39; is 12 to 19, and a pharmaceutically acceptable acid addition salt of said base and a therapeutically acceptable carrier therefore.

United States Patent Harfenist et al.

[ ANTI-TAPEWORM INFECTION COMPOSITION [72] Inventors: Morton Harfenist;Richard Baltzly,

both of Scarsdale, NY.

[73] Assignee: Burroughs Wellcome 8: Co. Notice: The portion of the termof this patent subsequent to Oct. 13, 1987,

has been disclaimed.

[22] Filed: May 25, 1970 [21] Appl. No.: 40,427

Related US. Application Data [63] Continuation-impart of Ser. No.672,984, Oct.

5, 1967, Pat. No. 3,534,142, which is a continuation-in-part of Ser. No.353,292, March 19, 1964, abandoned.

[30] Foreign Application Priority Data March 22, 1963 Great Britain ..il,555/63 [52] US. Cl ..424/326 [51] Int. Cl. ..A61k 27/00 [58] Field ofSearch ..424/326 [56] References Cited UNITED STATES PATENTS 3,290,37512/1966 Harfenist et al. ..424/326 [4 1*Sept. 26, 1972 3,462,537 8/1969Merk ..424/326 Primary Examiner-Sam Rosen Attorney-Dike, Thompson &Bronstein, Sewall P. Bronstein and Donald Brown 5 7 1 ABSTRACT An orallyingestible anti-tapeworm infection composition for mammals whichcomprises a therapeutically effective non-toxic amount of a compoundselected from the class consisting of a base of Formula (I) 23 Claims,No Drawings ANTl-TAPEWORM INFECTION COMPOSITION This application is acontinuation-in-part of U.S. Pat. application Ser. No. 672,984, filedOct. 5, 1967, now U.S. Pat. No. 3,534,142, which is acontinuation-inpart of U.S. Pat. application Ser. No. 353,292, filedMar. 19, 1964, now abandoned.

This invention relates to an orally ingestible composition to treattapeworm infestations in mammals.

In the complete specification of UK. Pat. No. 679,1 l9 (U.S. Pat. No.2,491,473) there are described and claimed substituted amidines havinglocal anaesthetic properties and possessing the Formula (I) wherein Rand R are alkyl groups containing together from four to 10 carbon atomsand R" is a lower alkyl group containing from one to four carbon atoms.

It has now been found that activity is shown against tapeworm (cestode)infections in mammals (as exemplified by activity against Hymenolepis mmin the mouse) by some of the higher members of the aforementionedamidines and their acid addition salts and, also, by a number of highernovel homologous amidines and their acid addition salts, as definedbelow. These amidines may be represented by the Formula (II) wherein Ris alkyl having from three to eight carbon atoms, R is alkyl having fromone to l 1 carbon atoms, preferably the sum of the carbon atoms of theRs and of R is 12 to 19 inclusive, and wherein both the Rs attached tothe nitrogen are similar and are the same.

This invention, therefore, provides a method for the treatment of atapeworm infestation, comprising the administration to a mammalian hostof such infestation of an amidine of the above formula or of an acidaddition salt thereof. While all of these amidines are relatively toxicon injection, the higher members are poorly absorbed and, hence, arerelatively non-toxic to the host when given orally. At the same time,the toxicity to the parasites also increases to a maximum around thecompounds in the middle of the class comprised in this invention. Forthis reason, these central members are preferred as combining lowertoxicity to the host with high effectiveness against the parasites. Theeffectiveness of individual compounds against individual parasitespecies varies somewhat, so that the compound of choice against oneparasite may not be that against another. Other factors to be consideredare the identity of the host and, especially when largescale treatmentof animal parasites is involved, the cost of preparing the compounds.

Tapeworm infections which may be conveniently treated with an amidine oran acid addition salt thereof include Echinococcus granulosus in dogs,D. mansoni or D. erinacci in dogs, cats or pigs, Monieza expansa insheep or cattle, Davainea proglottina in poultry, Raillietina tetragona,R. echinobothrida in poultry, Taenia taeniaformis in cats, T. hydatigenaor T. piszjformis in dogs, or T. saginata.

Of especial interest is a tapeworm of dogs, Echinococcus granulosis.This worm is virtually innocuous to its primary canine host, but itscysts cause much damage in the intennediate hosts-sheep, cattle anddeer. In various livestock raising regions, this parasite is both apublic health problem and a cause of considerable economic loss. Theonly effective way of dealing with it is to eliminate it from the dogsof the area.

In practice, the amidine compounds of this invention may be presentedfor the treatment of a tapeworm infection in the form of an orallyingestible pharmaceutical composition comprising an amidine or a saltthereof together with a therapeutically acceptable carrier therefor. Anamidine in the form produced in its chemical synthesis and its solutionsand suspensions in the liquids used therein is not, as such, apharmaceutical composition as defined in this specification. The amidineor a salt thereof may be presented advantageously in discreet units suchas tablets, capsules, cachets, each containing a predetermined amount ofthe compounds. It may be presented also as a powder or granules, as asolution or suspension in a non-aqueous or emulsified liquid.

The compositions may be made by any of the methods of pharmacy and mayinclude one or more of the following accessory ingredients: diluents,solutes, buffers, flavoring, binding, dispersing, surface-active,thickening, lubricating and coating materials, preservatives,antioxidants and bacteriostats, and any other acceptable excipients.

The preferred composition for the treatment of infections of tapewormsare tablets and granules comprising an amidine of the invention or asalt thereof wherein the Rs are the same. The compounds of Formula (II)or acid addition salts thereof are preferably orally administered in asingle dose at a dose level of 1 to 400 mg (l to 200 being preferred) asbase per kg of mammal (ie. dog, mouse, etc.) bodyweight. The preferreddosage for these compounds for treating Taenia pisiformis in dogs is 25to 50 mg/kg (as base) in a single orally administered dose, althoughmultiple doses may be administered.

In another aspect therefore, this invention provides an orallyingestible pharmaceutical composition for the treatment of a tapeworminfection comprising an amidine as previously defined.

The anthelmintic activity of the amidine acid addition salts lies in theamidine part of the molecule and the acid may be any acid which reactswith the amidine base to give a therapeutically acceptable acid additionsalt, for example: embonate, hydrochloride, hydrobromide, lactate,citrate, sulphate, succinate, oxalate, ptoluenesulphonate,2-hydroxy-3-naphthoate or pchlorobenzene sulphonate acid addition salts.

While the amidines can, in certain cases, be isolated as the base theyare fairly strong bases having pKa in the range 11-12 and, hence, willbe positively charged (that is, present as cation components of salts)under any conditions of physiological interest. If administered asbases, it would be expected that the acid gastric secretions wouldconvert them to salts. Furthermore, since the salts are very stablewhile the free bases are much less so, they will by practice be handled,stored and administered as acid addition salts.

An amidine of the invention may be prepared by a method similar to themethods described in the complete specification of U.K. Pat. No.619,659, namely by the reaction of a halomagnesium dialkylamine of theformula R N Mg X (X being a halogen atom) with the appropriate4-alkoxy-a-naphthonitrile and hydrolyzing the product.

The initial product of the reaction mixture is the halomagnesiumderivative of the amidine. This is hydrolyzed, for example, by an icedaqueous solution of ammonium chloride and the halomagnesium radical isreplaced by hydrogen, so liberating the required amidine. Usually thehydrolysis product is contaminated with secondary amine which is removedby distillation in vacuo or by other conventional means (such ascrystallization of the salts).

The halomagnesium radical is formed from a Grignard reagent and theappropriate secondary amine. Any Grignard reagent may be used as theGrignard hydrocarbon radical is eliminated as an inert hydrocarbon inthe formation of the halomagnesium secondary amine. The halogen may bechlorine, bromine or iodine, but bromine is preferred and ethylmagnesiumbromide has been found to be the most convenient reagent. These amidinesmay also be prepared, but in rather inferior yield, by the method ofBritish Pat. No. 598,453.

The following examples illustrate the invention. All temperatures are indegrees Celsius. 1n Examples to 13, the of 16, 20 and 100 correspond toaperture dimensions of l 130, 965 and 100 respectively.

EXAMPLE 1 Preparation of naphthamidine A Grignard solution was preparedfrom magnesium turnings (5 g.) and ethyl bromide (22 g., 0.2 mole) inabsolute ether (200 ml.) contained in a flask equipped with a stirrer,reflux condenser and dropping funnel. Di-n-amylamine (32 g.) was addedto this mixture at a rate sufficient to cause gentle refluxing and afterthe addition was complete, the solution was refluxed for a further hour.To the refluxed solution was added an ethereal solution of4-hexyloxy-a-naphthonitrile (38 g., 0.15 mole) over a period of 30minutes. After the addition was complete, the reaction mixture wasrefluxed for 24 hours, cooled and hydrolyzed with an iced hydrochloricacid solution. A considerable amount of solid separated and was filteredoff. The filtrate was extracted with ether, the extract discarded, theaqueous layer was treated with a base and extracted with ether. Theethereal extract formed Extract 1.

The solid originally obtained by filtration was dissolved in warm water,the solution then basified and extracted with benzene to form Extractll. Extracts I and II were then evaporated separately on a steam bathusing, if necessary, a vacuum to remove final traces of diamylamine. Thetwo basic residues were then dissolved in absolute ethanol and acidifiedwith ethanolic hydrogen chloride. Absolute ether was added until theN,N-diamyl-4-hexyloxy-asolutions were barely turbid, after whichcrystallization of the amidine hydrochloride was induced by scratching.The resulting salt melted at 2l7-218.

EXAMPLE 2 N,N-Diheptyl-4-butoxy-a-naphthamidine hydrochloride To asolution of ethyl magnesium bromide, prepared from magnesium turnings(3.7 g.) and ethyl bromide 16.3 g.) in anhydrous ether (200 ml.), wasadded di-nheptylamine (32 g.) in dry ether (150 ml.). The solution wasthen refluxed for an hour and 4-butoxy-anaphthanitrile (14.3 g.)dissolved in dry ether (250 ml.) was added gradually over one-half hour.The reaction mixture was then stirred and refluxed for 18 hours, cooledand hydrolyzed with iced saturated ammonium chloride solution. Theethereal layer was separated, washed with water and dried over anhydrouspotassium carbonate. This ethereal solution of the base was thenevaporated and the residue subjected to distillation at 0.03 to 0.05 mm.pressure. A portion of diheptylamine boiling at -93 was thus removed.The residue was dissolved in absolute ethanol, acidified with ethanolichydrogen chloride and crystallized by addition of ether. The purehydrochloride melted at 21 32 14.

EXAMPLE 3 N,N-Diheptyl-4-pentoxy-a-naphthamidine hydrochloride Thispreparation was-identical with that of Example 2, except that4-pentoxy-a-naphthonitrile (22.4 g.) was added to the solution ofbromomagnesium diheptylamide, and the reflux time was 19 hours. Theamidine hydrochloride, purified as described in Example 2, melted at207.

EXAMPLE 4 N,N-Dihexyl-4-butoxy-a-naphthamidine hydrochloride To asolution of ethyl magnesium bromide (prepared as in Example 2), wasadded dihexylamine (17.6 g.) anhydrous ether (150 ml.). After 45 minutesrefluxing, a solution of 4-butoxy-a-naphthonitrile (14.3 g.) was thenadded and the reaction mixture was stirred and refluxed for 24 hours.After working up by the method of Example 2, the pure hydrochloride,m.p. 2l8-219, was isolated.

EXAMPLE 5 N,N-Dihexyl-4-hexyloxy-a-naphthamidine hydrochloride AGrignard solution was prepared from magnesium turnings (4.85 g.) andethyl bromide (19.7 g.) in anhydrous ether (250 ml.). To this was addeda solution of di-n-hexylamine (40 g.) in anhydrous ether (220 ml.) andthe solution was refluxed for one-half hour. To this was added, over aperiod of 10 minutes, a solution of 4-hexyloxy-a-naphthonitrile (38 g.)in warm dry benzene ml.). The reaction mixture was stirred and refluxedfor 42 hours and then hydrolyzed with iced hydrochloric acid (containing60 ml. of concentrated hydrochloric acid). A solid separated thatappeared to contain the whole of the product together with somedihexylamine hydrochloride, the magnesium salts and any neutralimpurities being in the filtrate and EXAMPLE 6N,N-Dihexyl-4-heptyloxy-a-naphthamidine hydrochloride This preparationwas run by the same procedure as that of Example 5, except that4-heptyloxy-anaphthonitrile (40 g.) was used. The amidine hydrochloride,isolated by the same procedure, melted at l97-l 98, aftercrystallization from nitromethane.

EXAMPLE 7 N,N-Dioctyl-4-methoxy-a-naphthamidine hydrochloride Thiscompound was prepared by the method of Example 5, (using 27.5 g. of4-methoxy-anaphthonitrile). The amidine hydrochloride melted at 173.

EXAMPLE 8 N,N-Dibutyl-4-hexyloxy-a-naphthamidine hydrochloride AGrignard reagent was prepared from 22 g. (0.2 M) of ethyl bromide, 5.35g. (0.22 g-atom) of magnesium turnings (for Grignard) and 250 ml. ofcommercial anhydrous ether, under a nitrogen atmosphere. To this wasadded, over about 10 seconds, 31.3 g. (0.243 M) of dry, carbonate-freedi-n-butylamine, washing this in with about 50 ml. of anhydrous ether.The resulting mixture was stirred and heated under reflux about onehour. A solution of 47.8 g. (0.189 M) of 4-n-hexyloxyl-naphthonitrile inabout 250 ml. of hot benzene (previously dried by treatment with calciumhydride of material dried by azeotropic distillation) was then added,and the reaction mixture was heated under reflux for 19 hours. Cautiousaddition of 120 ml. of 6N aqueous hydrochloric acid after this time gavea white precipitate which was filtered off and combined with theether-benzene upper layer of the filtrate. The resulting suspension waslargely dissolved by addition of ethanol, treated with 120 ml. of 6Naqueous sodium hydroxide and extracted with ether. The ethereal solutionwas dried with magnesium sulfate and evaporated down, finally using amechanical pump and steam heat to distil off dibutylamine. The residuewas dissolved in a little ethanol and treated with a slight excess of aconcentrated solution of hydrogen chloride in ethanol, then ethylacetate and finally anhydrous ether to incipient turbidity. Two suchcrystallizations yielded 60 g. of white solid, mp. 2l42l4.8.

Anal. for C H ClN O, MW 419.04: C 71.63 H 9.38

Found: C 71.77 H 9.00

This compound has been shown to clear dogs of Dipylidium cqninum andTaenia pisiformis in single doses of mgjkg. In tests againstEchinococcus granulosis, complete clearance was obtained at 200 mg./kg.At this dose level, no toxic symptoms whatever were observed in thedogs.

EXAMPLE 9 A tablet of N,N-diheptyl-4-butoxy-a-naphthamidinehydrochloride was made from the following:

N,N-dihepty1-4-butoxy-a-naphthamidine hydrochloride 346 mg. Starch(potato) 50 mg. Lactose 100 ti 50 mg. Magnesium stearate 4 mg.

The hydrochloride salt was mixed with the lactose and 2/3 of the starchand the mixture granulated with sufficient 2 percent starch mucilagemade from the remainder of the starch. The moist mass was sifted througha 20 sieve and dried at 50. The dried mass was sifted 16 w and added tothe remainder of the starch and the magnesium stearate sifted 100 Theequivalent of 346 mg. of hydrochloride salt was compressed on a die tofonn a tablet.

EXAMPLE 10 Tablets of the following compound were made in the mannerdescribed in the preceding Example (9).

N,N-diamyl-4-hexyloxy-a-naphthamidine hydrochlorideN,N-diheptyl-4-butoxy-a-naphthamidine hydrochlorideN,N-di-n-heptyl-4-amyloxy-a-naphthamidine hydrochlorideN,N-dihexyl-4-butoxy-a-naphthamidine hydrochlorideN,N-dihexyl-4-hexyloxy-a-naphthamidine hydrochlorideN,Ndihexyl-4-heptyloxy-a-naphthamidine hydrochlorideN,N-dioctyl-4-methoxy-a-naphthamidine hydrochlorideN,N-dibutyl-4-butoxy-a-naphthamidine hydrochlorideN,N-dibutyl-4-amyloxy-a-naphthamidine hydrochlorideN,N-dibutyl-4-hexyloxy-a-naphthamidine hydrochloride EXAMPLE 1 lDispersible powder granules of N,N-diheptyl-4-butoxy-a-naphthamidinehydrochloride were made from the following:

N,N-diheptyl-4-butoxy-a-naphthamidine hydrochloride mg. Starch (Potato)90 mg. Magnesium stearate 1.0 mg.

EXAMPLE l2 Dispersible powder granules of the amidines named in Example10 were made in the manner described in Example 11.

EXAMPLE 13 To a Grignard reagent, prepared from magnesium turnings (4.85g.),ethyl bromide (19.7 g.) and ether (200 ml.) was addeddi-n-butylamine (28.1 g.) in dry ether (200 ml.). After an additionalhalf hour of heating under reflux, the amine magnesium salt solution soproduced was treated with 4-decyloxy-a-naphthonitrile (46.6 g.)dissolved in dried benzene (100 ml.). The reaction was heated underreflux for 1.5 days and then cooled and cautiously treated with anexcess of 6N- hydrochloric acid. The crystals so formed proved to becrude amidine hydrochloride contaminated with amidine hydrobromide whichremained even after several recrystallizations. The salt mixture wastherefore converted to the amidine base by dissolving in methanol andtreating this solution with excess of 30 percent aqueous sodiumhydroxide. This solution was then extracted with benzene and the benzenesolution was dried and distilled, finally at a bath temperature of 130and pressure 0.1 mm/l-lg. to remove unreacted amine. The residue wasdissolved in dry ether and treated with the requisite amount of dryhydrogen chloride, and the resulting crystals recrystallized twice fromacetone-ether, m. p. 196.

Analysis: Calculated for C, 72.1; H, 8.63; N, 6.5. Found: C, 72.03, H,9.34; N, 6.77.

EXAMPLE l4 N,N-Di-isopropyl-4-heptyloxy-a-naphthamidine A Grignardreagent was made from magnesium turnings (4.85 g., 0.2M) and ethylbromide (19.7 g., 0.18M) in commercial anhydrous ether (200 ml.) in theusual way. This was then heated under reflux for one-half hour anddi-isopropylamine (0.216M, 21.9 g.), previously dried over sodiumhydroxide pellets, dissolved in dry ether 100 ml.) was added. After anadditional hour of heating under reflux to ensure complete displacementof the active hydrogen of the amine to form the magnesium salt of theamine, 4-heptyloxy-anaphthonitrile (0.15M, 40.1 g.) dissolved in driedbenzene (100 ml.) was added with stirring. The reaction mixture was thenstirred and heated under reflux for two days, and protected from theatmosphere by a tube containing sodium hydroxide pellets serving as acondenser vent.

To the reaction mixture was cautiously first added water (100 ml.) andthen 6N-hydrochloric acid (100 ml.). During this addition, spontaneousrefluxing occurred. When the addition was completed the reaction mixturewas stored at 4 overnight and then filtered, yielding a pasty solid (75g.). A portion of this solid, after being dried on a porous plate,melted at 183 4. To remove the water and salts, the crude solid was dissolved in methanol and made alkaline by addition of 30% aqueous sodiumhydroxide (100 ml.). The resulting paste was shaken with benzene twice,causing nearly all of the solid to dissolve. The benzene solution wasseparated, dried over magnesium sulphate, and concentrated on a steambath. The residual solid weighed 43.4 g. It was dissolved in anhydrousether and cautiously treated with dry hydrogen chloride. When themaximum of precipitation had occurred, the

precipitate of the named amidine hydrochloride was filtered off,essentially pure, adjudged by its melting point of 203. Fourrecrystallizations from water by addition of aqueous hydrochloric acidto incipient turbidity at ca. 100 followed by cooling, gavehydrochloride salt, melting point 206.

Analysis: Calculated for C, 71.16; H, 9.21; Cl, 8.75.

Found: C, 70.72; H, 8.95; CI, 8.59.

EXAMPLE l5 N,N-Di-n-butyl-4-octyloxy-a-naphthamidine hydrochlorideDi-n-butylamine (387 g., 3 moles) and anhydrous aluminum chloride (201g., l.5 moles) were mixed in a three-liter flask. After the moderateheat of reaction had subsided, there was added solid4-octyloxy-anaphthonitrile (281 g.) which dissolved readily in the warmreaction mixture. The flask was protected from the atmosphere by acapillary outlet and was heated on the steam bath for three hours. Atthe end of that time, the reaction mixture was poured into iced 3N-hydrochloric acid (2 liter) with constant stirring. The precipitatedamidine hydrochloride was filtered off, washed with cold 3N-hydrochloricacid and recrystallized from hot water to giveN,N-dibutyl-4-octyloxy-anaphthamidine hydrochloride, m.p. l97-l98,identical with the material prepared by the method of Example 2.

( EXAMPLES 16 to 25 The following compounds, in the form of theirhydrochloride salts, were prepared in the manner described in Examples13 and 15. The melting points are given in degrees Celsius.

N,N-Di-n-propyl-4-heptyloxy-a-naphthamidine hydrochloride, 203203.5.

N,N-Di-n-butyl-4-heptyloxy-a-naphthamidine hydrochloride, 205.

N,N-Di-npropyl-4-octyloxy-a-naphthamidine hydrochloride hemihydrate,205.

N,N-Di-isopropyl-4-octyloxy-a-naphthamidine hydrochloride, 210.

N,N-Di-n-propyl-4-nonyloxy-a-naphthamidine hydrochloride, 206207.

N,N-Di-n-butyl-4nonyloxy-a-naphthamidine hydrochloride, 199.

N,N-Di-n-propyl-4-decyloxy-a-naphthamidine hydrochloride, l-l96.

N,N-Di-isopropyl4-decyloxy-anaphthamidine hydrochloride hydrate, l 86-l87.

N,N-Di-n-propyl-4-undecyloxy-a-naphthamidine hydrochloride, l86-l 87.

N,N-Di-isopropyl-4-undecyloxy-a-naphthamidine hydrochloride, 1 80l 81.

What is claimed:

1. An orally ingestible antitapeworm infection composition for mammalswhich comprises a therapeutically acceptable carrier and an effectivenon-toxic amount of a compound selected from the class consisting of abase of Formula (I) and a pharmaceutically acceptable acid addition saltof said base, in the above R is alkyl having from three to eight carbonatoms, R is alkyl having from 1 to ll carbon atoms, wherein both the Rsattached to the nitrogen atom are the same and in which the sum of thecarbons in Rs and R is 12 to 19. t

2. A composition according to claim 1 in the form of a tablet, capsule,or cachet.

3. A composition according to claim 1, in which R is amyl and R ishexyl.

4. A composition according to claim I, in which R is heptyl and R isbutyl.

5. A composition according to claim 1, in which R is heptyl and R ispentyl.

6. A composition according to claim 1, in which R is hexyl and R isbutyl.

7. A composition according to claim 1, in which R is hexyl and R ishexyl.

8. A composition according to claim 1, in which R is hexyl and R isheptyl.

9. A composition according to claim 1, in which R is octyl and R ismethyl.

10. A composition according to claim 1, in which R is butyl and R ishexyl.

11. A composition according to claim 1, in which R is butyl and R isbutyl.

12. A composition according to claim 1, in which R is butyl and R isamyl.

13. A composition according to claim 1, in which R is butyl and R isdecyl.

14. A composition according to claim 1, in which R is isopropyl and R isheptyl.

15. A composition according to claim 1, in which R is butyl and R isoctyl.

16. A composition according to claim 1, in which R is propyl and R isheptyl.

17. A composition according to claim 1, in which R is butyl and R isheptyl.

18. A composition according to claim 1, 1n WhlCh R is propyl and R isoctyl.

19. A composition according to claim 1, in which R is propyl and R isnonyl.

20. A composition according to claim 1, in which R is butyl and R isnonyl.

21. A composition according to claim 1, in which R is propyl and R isdecyl.

22. A composition according to claim 1, in which R is propyl and R isundecyl.

23. A composition according to claim 10 in the form of a tablet, capsuleor cachet.

2. A composition according to claim 1 in the form of a tablet, capsule,or cachet.
 3. A composition according to claim 1, in which R is amyl andR'' is hexyl.
 4. A composition according to claim 1, in which R isheptyl and R'' is butyl.
 5. A composition according to claim 1, in whichR is heptyl and R'' is pentyl.
 6. A composition according to claim 1, inwhich R is hexyl and R'' is butyl.
 7. A composition according to claim1, in which R is hexyl and R'' is hexyl.
 8. A composition according toclaim 1, in which R is hexyl and R'' is heptyl.
 9. A compositionaccording to claim 1, in which R is octyl and R'' is methyl.
 10. Acomposition according to claim 1, in which R is butyl and R'' is hexyl.11. A composition according to claim 1, in which R is butyl and R'' isbutyl.
 12. A composition according to claim 1, in which R is butyl andR'' is amyl.
 13. A composition according to claim 1, in which R is butyland R'' is decyl.
 14. A composition according to claim 1, in which R isisopropyl and R'' is heptyl.
 15. A composition according to claim 1, inwhich R is butyl and R'' is octyl.
 16. A composition according to claim1, in which R is propyl and R'' is heptyl.
 17. A composition accordingto claim 1, in which R is butyl and R'' is heptyl.
 18. A compoSitionaccording to claim 1, in which R is propyl and R'' is octyl.
 19. Acomposition according to claim 1, in which R is propyl and R'' is nonyl.20. A composition according to claim 1, in which R is butyl and R'' isnonyl.
 21. A composition according to claim 1, in which R is propyl andR'' is decyl.
 22. A composition according to claim 1, in which R ispropyl and R'' is undecyl.
 23. A composition according to claim 10 inthe form of a tablet, capsule or cachet.